【药物名称】Vancomycin hydrochloride, Vancocin Pulvules, Vancomycin Enterocaps, Vancomycin CP, Vancocine, Vanconcina A.P., Vancocin
化学结构式(Chemical Structure):
参考文献No.540227
标题:Synthesis of vancomycin from the aglycon
作者:Thompson, C.; et al.
来源:J Am Chem Soc 1999,121(6),1237
合成路线图解说明:

A formal total synthesis of vancomycin has been reported. The known aglycon of vancomycin (I) was protected at the amino group as the allyloxy- carbonyl derivative (III) using allyloxycarbonyl succinimide (II). Then, carboxylate group was converted to allyl ester (V) with allyl bromide (IV) and KHCO3.

合成路线图解说明:

Selective protection of the phenol group of (V) with p-methoxybenzyl chloride (VI) gave benzyl ether (VII), and the remaining phenol groups of (VII) were further alkylated with allyl bromide to afford (VIII).

合成路线图解说明:

After acetylation of the benzylic alcohols of (VIII), deprotection of the p-methoxybenzyl group with TFA furnished the protected aglycon (IX). Glycosylation with the protected glucopyranose sulfoxide (X) was effected in the presence of triflic anhydride, 2,6-di-tert-butyl-4-methylpyridine, and boron trifluoride etherate to produce (XI).

合成路线图解说明:

Then, the azidobutirate ester of (XI) was selectively removed with PPh3, and the resulting intermediate (XII) was condensed with the protected vancosamine sulfoxide (XIII) to give the protected vancomycin (XIV).

合成路线图解说明:

Subsequent deacetylation with hydrazine produced (XV), from which the allyl and allyloxycarbonyl groups were finally removed by treatment with tributyltin hydride and palladium catalyst.

参考文献No.555311
标题:Total synthesis of the vancomycin aglycon
作者:Boger, D.L.; et al.
来源:J Am Chem Soc 1999,121(43),10004
合成路线图解说明:

The cyclization of tripeptide derivative (XII) (assembled n three steps from the corresponding amino acids) by means of K2CO3/CaCO3 gives the macrocyclic peptide (XIII), which was reduced at its NO2 group with H2 over Pd/C and treated with tert-butyl nitrite, HBF4 and CuCl2 to obtain the corresponding chloro derivative (XIV). The condensation of (XIV) with the boronic acid derivative (XV) by means of a Pd catalyst affords the biphenyl derivative (XVI), which is desilylated with Bu4NF giving the secondary alcohol (XVII). The hydrolysis of the methyl ester of (XVII) with LiOH yields the corresponding carboxylic acid (XVIII).

合成路线图解说明:

Selective deprotection of the benzyloxycarbonylamino group of (XVIII) with H2 over Pd/C gives the corresponding amino derivative (XIX), which is cyclized by means of EDC and HOBT yielding the bicyclic peptide (XX). Elimination of the Boc protecting group of (XX) with formic acid affords the primary amine (XXI), which is acylated with the previously obtained dipeptide intermediate (XI) by means of DEPBT providing the adduct (XXII).

合成路线图解说明:

The cyclization of tripeptide derivative (I) (assembled in three steps from the corresponding amino acids) by means of K2CO3/CaCO3 gives the macrocyclic peptide (II), which was reduced at its NO2 group with H2 over Pd/C and treated with tert-butyl nitrite, HBF4 and CuCl2 to obtain the corresponding chloro derivative (III). The condensation of (III) with the boronic acid derivative (IV) by means of a Pd catalyst affords the biphenyl derivative (V), which is desilylated with Bu4NF, giving the secondary alcohol (VI). The hydrolysis of the methyl ester of (VI) with LiOH yields the corresponding carboxylic acid (VII).

合成路线图解说明:

Selective deprotection of the benzyloxycarbonylamino group of (VII) with H2 over Pd/C gives the corresponding amino derivative (VIII), which is cyclized by means of EDC and HOBT, yielding the bicyclic peptide (IX). Elimination of the Boc protecting group of (IX) with formic acid affords the primary amine (X) , which is acylated with the tripeptide intermediate (XI) by means of EDC and HOAt, providing the adduct (XII).

合成路线图解说明:

The cyclization of (XII) by means of CsF in DMSO gives the tris macrocyclic compound (XIII), which is reduced at the NO2 group with H2 over Pd/C, yielding the amino derivative (XIV). The diazotation of (XIV) with t-Bu-ONO and HBF4, followed by reaction with CuCl2/CuCl, affords the corresponding chloro derivative (XV), which is silylated with Tbdms-N(Me)-COCF3 to provide the bis silyl ether (XVI).

合成路线图解说明:

Elimination of the Mem protecting group of (XVI) by treatment with borane (XVII) gives the primary alcohol (XVIII), which is oxidated to the corresponding acid with DMP and NaClO2 and simultaneously methylated with Tms-CHN2 to yield the methyl ester (XIX). The controlled hydrolysis of the cyano group of (XIX) with H2O2 and K2CO3 affords the corresponding amide (XX), which is finally desilylated with TBAF and demethylated with AlBr3 to furnish the target aglycon.

参考文献No.600206
标题:Diasteroselective total synthesis of the vancomycin aglycon with ordered atropisomer equilibrations
作者:Boger, D.L.; et al.
来源:J Am Chem Soc 1999,121(13),3226
合成路线图解说明:

Assembly of the target compound: The condensation of the carboxylic acid intermediate (XXI) with the free amino group of the intermediate cyclopeptide (XXII) by means of DEPBT gives the corresponding amide (XXIII), which is cyclized by means of CsF in DMSO yielding the macrocyclic ether (XXIV). The reduction of the nitro group of (XXIV) with H2 over Pd/C affords the corresponding amino derivative (XXV).

合成路线图解说明:

The cyclization of tripeptide derivative (I) (assembled in three steps from the corresponding amino acids) by means of K2CO3/CaCO3 gives the macrocyclic peptide (II), which was reduced at its NO2 group with H2 over Pd/C and treated with tert-butyl nitrite, HBF4 and CuCl2 to obtain the corresponding chloro derivative (III). The condensation of (III) with the boronic acid derivative (IV) by means of a Pd catalyst affords the biphenyl derivative (V), which is desilylated with Bu4NF, giving the secondary alcohol (VI). The hydrolysis of the methyl ester of (VI) with LiOH yields the corresponding carboxylic acid (VII).

合成路线图解说明:

Selective deprotection of the benzyloxycarbonylamino group of (VII) with H2 over Pd/C gives the corresponding amino derivative (VIII), which is cyclized by means of EDC and HOBT, yielding the bicyclic peptide (IX). Elimination of the Boc protecting group of (IX) with formic acid affords the primary amine (X) , which is acylated with the tripeptide intermediate (XI) by means of EDC and HOAt, providing the adduct (XII).

合成路线图解说明:

The cyclization of (XII) by means of CsF in DMSO gives the tris macrocyclic compound (XIII), which is reduced at the NO2 group with H2 over Pd/C, yielding the amino derivative (XIV). The diazotation of (XIV) with t-Bu-ONO and HBF4, followed by reaction with CuCl2/CuCl, affords the corresponding chloro derivative (XV), which is silylated with Tbdms-N(Me)-COCF3 to provide the bis silyl ether (XVI).

合成路线图解说明:

Elimination of the Mem protecting group of (XVI) by treatment with borane (XVII) gives the primary alcohol (XVIII), which is oxidated to the corresponding acid with DMP and NaClO2 and simultaneously methylated with Tms-CHN2 to yield the methyl ester (XIX). The controlled hydrolysis of the cyano group of (XIX) with H2O2 and K2CO3 affords the corresponding amide (XX), which is finally desilylated with TBAF and demethylated with AlBr3 to furnish the target aglycon.

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